In searching for the causes of obesity among Pima Indians, we have identified five metabolic predictors of body weight gain: a low "relative" metabolic rate, a low fat/carbohydrate oxidation ratio, a low spontaneous physical activity, insulin sensitivity and, recently, a low sympathetic nervous system (SNS) activity. All these predictors aggregate in families and seem to be heritable. They have been used as subphenotypes to search for genetic loci underlying the susceptibility to obesity. Since Pima Indians have a low sympathetic nervous system activity, and glucocorticoids may inhibit SNS activity, we measured SNS and hypothalamic-pituitary-adrenal (HPA) axis activities in 39 non-diabetic men, 20 Pimas and 19 Caucasians. The activity of the HPA axis was similar in the two groups, indicating that the lower SNS activity in Pima Indians may be the result of a higher sensitivity of the SNS to the inhibitory effect of glucocorticoid i.e. a functional hypercortisolism. We are presently testing this hypothesis. Due to the fact that a low fat/carbohydrate oxidation ratio is predictive of weight gain, we have investigated whether Pima Indians have lower lipolytic responses to stimuli such as exercise, mental stress and local administration of isoproterenol than Caucasians. By microdialysis technique we could not identify an impaired lipolytic response to the above stimuli in Pima Indians. However, among Pima Indians, 24-h respiratory quotient was found to be inversely related to the in situ adipose tissue lipolytic response to beta adrenergic stimulations in males. The results suggest that impaired beta adrenergic lipolytic response may contribute to a low rate of fat oxidation in some individuals and predispose them to weight gain. Finally, using positron emission tomography (PET) we are presently studying the neuroanatomical areas of the brain involved in hunger and satiation in humans. Preliminary findings suggest that obese individuals have an attenuated cerebral blood flow increase in the anterior cingulate during hunger and an attenuated blood flood increase in the lateral prefrontal cortex during satiation. These studies provide new information about the regions of the human brain involved in the regulation of hunger and satiation, and those that may selectively contribute to the hyperphagia associated with obesity.